Fuchs' endothelial corneal dystrophy (FECD; MIM136800) is a common disease affecting approximately 1% of the general US population. Initially asymptomatic, individuals eventually present with decreased vision, foreign body sensation and pain upon waking. Slit lamp (microscopic) examination initially shows focal thickenings of the Descemet's membrane known as corneal guttae, with subsequent stromal edema (swelling), epithelial edema, and in advanced stages, painful bullous keratopathy. FECD is a common indication for corneal transplantation alone or in combination with cataract surgery. In addition, individuals undergoing cataract surgery with FECD are at significant risk for corneal decompensation requiring subsequent corneal transplantation. Molecular data on the genetic basis of corneal dystrophies is limited. With a significant population at risk, the identification of the gene(s) that may contribute to the dystrophy would be very useful for counseling, implementation of standard methods for therapeutic intervention, and ultimately gene modulation and/or therapy. In this application, we propose to use the network built by the active, multi-center NEI-funded Cornea Donor Study (CDS) as the nexus to identify 500 families with FECD using the consortium model. In Aim 1 we will identify cases with advanced FECD and characterize the extent of familial clustering using a clinical measure of severity as a semi-quantitative trait. Family history, clinical, and other demographic information will be collected using a standardized instrument. Histopathologic confirmation of advanced index cases will be obtained. Blood samples will be collected for molecular genetic analyses. A web-based database is being constructed to facilitate multi-site data collection. In Aim 2 a genome-wide scan will be conducted utilizing DMA collected from the index cases and families (N = 500 families; estimated N is equal to or >: 500 sib pairs). Model-free linkage analysis will be conducted using the DMA marker data in conjunction with the clinical data on FECD to identify linkage signals. To confirm evidence of linkage and to narrow the initial interval, additional markers will be typed in regions that demonstrate moderate to significant evidence of linkage (p is equal to or <0.05; LOD score equals approximately 0.8). In Aim 3 candidate genes identified through previous investigations of a limited number of families (e.g. COL8A2) will be examined for mutations. Thus, we will investigate the importance of these genes on a more global basis by characterizing their role in a larger sample. We anticipate that this study will lead to novel insights into the etiology of FECD and the biology of the corneal endothelium.